The APOE gene - which encodes Apolipoprotein E – has been extensively studied due to its biological relevance to a range of neurological and cardiovascular diseases, including Alzheimer’s Disease (AD). In addition to the roles APOE plays in developmental diseases such as AD, additional studies have shown APOE to be implicated in the host response to a range of infectious pathogens, including herpes simplex virus type I (HSV1) and hepatitis C virus (HCV).
As has been widely demonstrated with the COVID-19 pandemic, infectious agents may often elicit diverse responses based on attributes of the host organism. Exposure to SARS-CoV-2 and subsequent viral infection can lead to the development of COVID-19 – a disease which varies from asymptomatic cases to a severe, life-threatening respiratory illness. In addition to the ACE2 gene, researchers have begun to identify additional genes that may be associated with disease severity. Beyond this eminent example, several common viruses can cause serious neurological disease years after initial infection.
A similar range of disease severity may be seen in other infectious agents, such as hepatitis C virus (HCV). Growing evidence supports the theory that host genetics are a factor in determining both susceptibility to and outcome of infections, which is exemplified by the APOE isoforms. In 1997, the lab of Dr. Ruth Itzhaki was among the first to study the role of specific APOE alleles for their involvement in a range of diseases caused by infectious agents. Since this time, related evidence has suggested that certain APOE isoforms, such as carriers of an APOE-e4 allele, may confer various influences on pathogenic infectivity, disease severity, and even overall damage caused by infection.
APOE is a polymorphic gene with three (3) major alleles (APOE-ε2, APOE-ε3, and APOE-ε4) encoding three protein isoforms (apoE2, apoE3, and apoE4). The significance of the APOE4 variant as the single largest genetic risk factor (yet not a direct determinant) for late-onset AD among the human population was discussed in our recent Gene of the Week article. In addition to the roles APOE plays in developmental diseases such as AD, additional studies have shown APOE to be implicated in the host response to a range of infectious pathogens, including herpes simplex virus type I (HSV1) and hepatitis C virus (HCV).
A 2020 study by Kuo et al.5 assessed the possible link between APOE-e4 and COVID-19 severity. They found that APOE-ε4 homozygotes had an increased risk of severe COVID-19 infection, an association that remained even after removing participants with APOE-ε4 associated conditions linked to COVID-19 severity. Several studies by the lab of Dr. Itzhaki have revealed the APOE genotype to have a modulatory effect on either susceptibility to or severity of damage by the pathogen in several infectious diseases, such as HSV1. One potential explanation for the results of the study by Kuo et al. is that the heparan sulphate proteoglycan (HSPG)-receptor binding domain of apoE attaches to the same non-specific receptors as initially may be bound by SARS-CoV-2 (before proceeding to the main ACE2 receptor). Unique APOE isoforms may compete to different extents with SARS-CoV-2 for binding of these HSPGs. With the emerging evidence that APOE-e4 homozygosity is a risk for severe cases of COVID-19, more research is necessary to understand the mechanism of action as well as influences of additional APOE isoforms on COVID-19.
In response to our recent publication covering the connections between Alzheimer’s Disease (AD) and APOE, Dr. Itzhaki contacted us with more information about her research, including the connections between apoE isoforms, viral pathologies, and even Alzheimer’s Disease (AD). The results shown by the lab of Dr. Itzhaki, supported by many others since, indicate that a virus plays a major role in AD. It should be noted that this viral concept does not preclude a major role of amyloid-β (Aβ) and P-tau in AD etiology; rather, this work suggests HSV1 infection to be a contributing factor in their accumulation.
Dr. Ruth F Itzhaki attended London University to earn several degrees: a BSc in physics, an MSc in Biophysics - being awarded one of the only two studentships then available in the subject - and finally a PhD in Biophysics. After studying a diverse array of research topics, Dr. Itzhaki eventually came to focus on Alzheimer's disease: initially, on defective DNA repair and aluminum, and later, wholly on the role of viruses acting along with a genetic factor in dementia. For her work in Neurovirology, Dr. Itzhaki won an Investigator award from the Lancet, a Wellcome Trust Innovative award, two Olympus Foundation awards, an Alzheimer's Research Forum award, and a Manchester City Council award. Stemming from the studies on Alzheimer’s Disease (AD), she investigated the role of APOE in determining the outcome of pathogenic infection.3 She is a Professor Emerita in Manchester University and an Honorary Visiting Professorial Fellow in Oxford University.
“I enjoyed reading your article on APOE and wonder if you know that APOE has been implicated in a range of diseases caused by infectious agents. My lab was the first to study this topic. It arose from our discovery in 1991 (Jamieson et al. J Med Virol) that HSV1 is present in brain of many elderly people and that in carriers of an APOE-e4 allele, the virus and the genetic factor together confer a strong risk of Alzheimer’s disease (Itzhaki et al., Lancet, 1997; see also review: Itzhaki, Frontiers Aging Neurosci., 2018). We also found a striking parallelism in that APOE-e4 is a risk for cold sores – herpes labialis - which is usually caused by HSV1. Our data show that APOE does not determine susceptibility to HSV1 infection but instead determines the extent of damage caused by the virus – ranging from asymptomatic to fatal (so that some people are infected but not affected). To explain our discovery, we suggested that apoE protein competes with the virus for binding to certain cell surface receptors for entry into cells, and that apoE4 might compete less well than the other isoforms, hence allowing more HSV1 entry and therefore more damage. Alternatively, [apoE isoforms might impact] repair of virus-induced damage, with repair being less efficient in apoE-4 carriers.
That lead us to examine other disease-causing infectious pathogens that bind to the same receptors in the cell surface as does apoE. We investigated that possibility in several infectious diseases, the most detailed one being liver disease caused by hepatitis C virus (HCV). We discovered that in this case APOE-e4 was strongly protective against liver damage, as judged by three different criteria (Wozniak et al., Hepatology, 2002). No allele was protective against infection by HCV, as is the case with HSV1. Whether the apoE effect depends on cell type – involving specific receptors - or whether, perhaps, the effect instead involves repair of virus-induced damage, with repair being less efficient in carriers of a specific allele, is unknown.“
———— Professor Ruth F Itzhaki
It is estimated that as many as 44 million people worldwide are affected by Alzheimer’s disease (AD) or a related form of dementia - the numbers continue to rise with increasing longevity. To date, there are no efficient prevention nor treatment options available. Although the exact cause of AD is unknown, the amyloid plaques and neurofibrillary tangles – abnormal brain features characterizing this disease – are of particular interest in current research efforts.
In addition, many researchers are also focusing on genetic testing. For example, there are studies comparing the DNA information of tens of thousands of AD patients with other elderly people who are not sick, to screen out genes that may be related to the onset of AD. Genetic studies have been used to identify mutation sites related to AD - and subsequently implement gene knockout, point mutation, and/or transgenic animal models to further verify whether these genes or specific mutations can cause AD.
Regarding the pathogenesis of Alzheimer’s Disease (AD), researchers have also put forward other hypotheses, among which, inflammation is considered an important cause. In the later stages of Alzheimer's disease, the brain's immune cells (called microglia) enter a hyperactive state, killing neurons. Some researchers believe that this is the cause of most symptoms of dementia, which means that inflammation could be a valuable direction. As discussed in our 2017 article, “Is ApoE the Key to an Alzheimer’s Cure?”, researchers showed that ApoE affects inflammation and tau-mediated neurodegeneration independently of amyloid-β pathology. Their data suggest that the ApoE4 variant is a gain-of-function mutation that causes increased neurodegeneration in response to tau neurofibrillary tangles. The other ApoE variants have reduced neurodegeneration, while mice lacking ApoE entirely showed virtually no Alzheimer’s-like neurodegeneration. In vitro co-culturing studies
studies suggested that ApoE (particularly ApoE4) mediates neurodegeneration by initiating a harmful immune response.
Given that infections by pathogens are often associated with inflammation and related damage, it may be seen how some researchers believe that certain infections can confer increased risk of Alzheimer’s disease (AD). A study published by Ruth Itzhaki in 1997 showed that the combination of HSV1 infection in brain and APOE-ε4 allele confers a high risk of AD. Upon substantiating HSV1 viral presence and activity in the brain of patients living with AD, results suggested that HSV1 and APOE-e4 together are particularly harmful in the nervous system. Additionally, as in the peripheral nervous system, it is thought that HSV1 reactivates from latency in brain (during immunosuppression, stress etc.) causing localized damage which is greater in APOE-e4 carriers. Dr. Itzhaki has indicated the potential for antiviral treatments to slow deterioration in those afflicted, and vaccination to prevent onset of AD.
Recently, there has been an influx of strong evidence supporting the concept that that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer’s disease (AD). This includes the proposal that latent HSV1 in the brains of APOE-e4 allele carriers is reactivated intermittently – such as by immunosuppression, stress, inflammation, peripheral infection – which results in accumulation of damage that eventually culminates in the development of AD. Dr. Itzhaki’s 2018 publication, Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease, noted the range of studies connecting viruses and disease states:
“... with the over 150 [now over 300 as of Jan. 2021] publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD. Three other studies are described which directly relate to HSV1 and AD: they deal respectively with lysosomal changes in HSV1-infected cell cultures, with evidence for a role of human herpes virus type 6 and 7 (HHV6 and HHV7) in AD, and viral effects on host gene expression, and with the antiviral characteristics of beta amyloid (Aβ). Three indirectly relevant studies deal respectively with schizophrenia, relating to antiviral treatment to target HSV1, with the likelihood that HSV1 is a cause of fibromyalgia (FM), and with FM being associated with later development of SD. Studies on the link between epilepsy, AD and herpes simplex encephalitis (HSE) are described also, as are the possible roles of APOE-ε4, HHV6 and HSV1 in epilepsy.”1
Despite the evidence of latent HSV infections correlating with increased risk of neurodegeneration, there have been few animal studies focused on evaluating long-term HSV infection in the CNS. One ongoing study has evaluated long term-HSV latency in human-APOE-e4 (huApoE4) targeted transgenic mice. Among the tests performed at 12 months post infection, significant differences were seen in Morris Water Maze (MWM) that suggested altered hippocampal function. Furthermore, “examination of hippocampal region revealed an ~8-fold increase in focal Aβ deposits.” 2 Although the combined results suggest a solid link between huApoE4-related cognitive impairment and long term HSV latent infection, more studies are needed.
Given that different model development strategies may generate different results, many researchers use multiple models in their research or combine gene-edited mice with other methods to produce composite models to better study AD.
For decades, beta-amyloid (Aβ) has dominated AD research—perhaps at the expense of other valuable ideas. As multiple drugs based on the amyloid hypothesis have been "defeated" in clinical trials in recent years, some researchers believe that it is time to explore alternative ways. The research on Alzheimer's disease has a long way to go. It is hoped that scientists and pharmaceutical companies will overcome the difficulties as soon as possible and bring hope to patients and their relatives.
As researchers learn more about AD, people are becoming more aware that effective treatment needs to target multiple factors, including genetics, immune system, and lifestyle. Early intervention may be the key to successful treatment.
The use of custom mouse models could provide much more clarity to these disease states by more accurately representing the human system(s) of significance for each study. This is especially critical for the broader range of invasive therapeutics; establishing an effective animal model for a particular study can provide significant savings (time & budget) over the long-term by quickly providing in vivo proof of concept & feasibility data.
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1. Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease - https://doi.org/10.3389/fnagi.2018.00324
3. Biography: https://www.research.manchester.ac.uk/portal/ruth.itzhaki.html
4. Itzhaki RF, Wozniak MA. Apolipoprotein E: Microbial Friend or Foe?. In: Apoprotein Research, Eds: LR Penfield and RT Nelson 2009. Nova Science Publishers Inc., New York.
5. Kuo C-L, Pilling LC, Atkins JL, et al. APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort. Journals Gerontology Ser. 2020:glaa131-. doi:10.1093/gerona/glaa131.